DNA repair/replication transcripts are down regulated in patients with Fragile X Syndrome

Abstract

BackgroundFragile X Syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene, with disease classification based on the number of CGG repeats. The mechanisms of repeat expansion are dependent on the presence of cis elements and the absence of trans factors both of which are not mutually exclusive and contribute to repeat instability. Expansions associated with trans factors are due to the haploinsuffient or reduced expression of several DNA repair/metabolizing proteins. The reduction of expression in trans factors has been primarily conducted in animal models without substantial examination of many of these expansion mechanisms and trans factors in humans.ResultsTo understand the trans factors and pathways associated with trinucleotide repeat expansion we have analyzed two microarray datasets which characterized the transcript expression in patients with FXS and in controls.ConclusionWe observed significant down regulation of DNA damage/repair pathway transcripts. This observation was consistent in both datasets, which used different populations. Within these datasets, several transcripts overlapped in the direction of association and fold change. Further characterization of these genes will be critical to understand their role in trinucleotide repeat instability in FXS.

Seeking for potential pathogenic genes of major depressive disorder in the Gene Expression Omnibus database

“…The over‐expression of 8‐oxoguanine DNA glycosylase (OGG1) is the hallmark of the normal brain aging (Lu et al, ). It is reported that the interaction between OGG1 and X‐ray repair cross complementing 1 has been implicated in schizophrenia (Derakhshandeh, Saadat, Farrashbandi, & Saadat, ; Odemis et al, ; Psimadas et al, ; Saadat, Pakyari, & Farrashbandi, ) and autism spectrum disorder (Shpyleva et al, ; Xu, Rosales‐Reynoso, Barros‐Nunez, & Peprah, ; Young, McKinney, Ross, Wahle, & Boyle, ). It is found that the expression of OGG1 is increased in white matter oligodendrocytes of patients with MDD (Szebeni et al, ).…”

Annual Research Review: The (epi)genetics of neurodevelopmental disorders in the era of whole‐genome sequencing – unveiling the dark matter

“…As such, ADHD presents itself in personality traits ranging from mild phenotypic expression of maladaptive behaviour to severe psychopathology. Increased creativity (White & Shah, ), (social) intuition and leadership skills (Fernández‐Mayoralas, López‐Arribas, Muñiz‐Borrega, & Prados‐Parra, ) are also reported for subclinical forms of ADHD, highlighting an evolutionary psychobiological perspective for positive selection and maintenance of ADHD‐related traits in populations (also see Section 5) (Ding et al., ; Matthews & Butler, ; Swanson et al., ).…”

“…While the pertinent definition of ADHD as a dimensional disorder of deficits with an admixture of potentially beneficial traits has evolved from a more categorical diagnostic and treatment‐based view, it is increasingly realized that some forms of ADHD may still be a segment, albeit at the extreme, of the continuum of normal behaviour (Angold, Erkanli, Egger, & Costello, ; Eisenberg, ). Potential beneficial traits for ADHD include, but might not be limited to, levels of energy and creativity (Bergson, Ansell‐Pearson, & Mullarkey, ; Healey & Rucklidge, ), multitasking, out‐of‐the‐box thinking, enthusiasm in social interaction and positive emotionality (Fernández‐Mayoralas et al., ; White & Shah, ). A historically recent positive selection of DRD4 alleles associated with novelity seeking and risk taking, but also a risk factor for the development of ADHD was detected in several studies (Ding et al., ; Matthews & Butler, ; Swanson et al., ).…”

“…As discussed earlier, rare de novo mutations are suspected to partially explain the missing heritability as an apparent paradox in behavioural genetics. Various findings in patients with FXS indicate down‐regulated DNA repair/replication in gene transcripts (Xu, Rosales‐Reynoso, Barros‐Núñez, & Peprah, ). It is speculated that down‐regulation of such pathways itself could have built up an increased genetic risk in affected families, making them susceptible to gene‐specific repeat expansions.…”

High expression of miR‐510 was associated with CGG expansion located at upstream of FMR1 into full mutation

“…[3][4][5] More than half of miRNA genes have been identified in different fragile sites. 6 The studies indicated that the incidence of miRNAs was high in fragile sites within 16,19, and X chromosomes. The distribution of miRNAs in unstable regions and fragile sites suggested that it is likely that miRNAs could be involved in different diseases.…”